After penicillin was used clinically in 1940, thousands of antibiotics have been developed, and also hundreds are commonly used in clinical practice. In 2006, among the 500 best-selling drugs in the world, there were 77 anti-infective drugs, which were the first of 19 categories of drugs. Due to wide use of antibiotics in clinical practice, drug resistance has been gradually evolved in bacteria, causing that more and more antibiotics lose their effectiveness gradually.
Vancomycin is a glycopeptide antibiotic produced by the Streptomyces orientalis strain. It was approved by US FDA for clinical use in 1958, effective mainly against Gram-positive bacteria with strong antibacterial activity, and was ever deemed as the last line of defense for human being against bacterial infections. Until 1990s, i.e. after vancomycin had been used for nearly 40 years, bacteria resistant to vancomycin were found and caused panic in the medical field. Therefore, there is an urgent need for discovery and modification of antibiotics.
During modification of vancomycin in a lone time period, scientists from Eli Lilly found in WO9630401A1 that introduction of an aliphatic or aromatic chain into the polysaccharide moiety of such compounds can improve their activities greatly and even show a very good inhibitory effect against drug-resistant bacteria, e.g. Oritavancin as shown by the following formula:

“Synthesis of Vancomycin from the Aglycon.” J. Am. Chem. Soc. 1999, 121, 1237-1244 demonstrated that vancomycin derivatives modified by a long chain show dual mechanisms of action in the bacteria-killing process: in addition to the original binding mechanism of the polypeptide moiety, the polysaccharide moiety is able to inhibit the glycosyl transferase involved in the process of synthesizing cell wall. These two mechanisms are complementary each other so as to reach the objective of enhancing the activity significantly.
However, with introduction of the aliphatic and aromatic chains, the liposolubility (Log P) of such novel compounds increases greatly, and thus binding to ion channels as well as toxic and side effects on the cardiovascular system also increase, which may be adverse to the cardiovascular system.